Compounds, systems, and methods for monitoring and treating a surface of a subject

ABSTRACT

Compounds, systems, and methods are provided for the design and assembly of a non-invasive, analyte sensing dressing. The dressing can be therapeutic. The dressing includes a sensor and a matrix. The sensor is capable of detecting analytes such as molecular oxygen, carbon dioxide, nitric oxides, dissolved analytes in plasma, and hydrogen ions. The matrix is at least partially permeable to the analyte. The device emits a detectable signal when the sensor is excited in the presence of the analyte. In one version of the dressing, the sensor includes a meso-unsubstituted metallated porphyrin that is sensitive towards oxygen. The metallated porphyrin can be excited when illuminated at a first wavelength, followed by emission of phosphorescence at a second wavelength whose intensity can be used as an indicator for oxygen concentration.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/787,480 filed Feb. 11, 2020, which is adivisional application of U.S. patent application Ser. No. 16/054,028filed Aug. 3, 2018, now U.S. Pat. No. 10,905,780, which is a divisionalapplication of U.S. patent application Ser. No. 15/684,040 filed Aug.23, 2017, now U.S. Pat. No. 10,039,842, which is a divisionalapplication of U.S. patent application Ser. No. 14/903,710 filed Jan. 8,2016, now U.S. Pat. No. 9,789,206, which is a 371 application ofPCT/US2014/042377 filed Jun. 13, 2014, which claims priority from PCTInternational Application No. PCT/US2013/049847 filed Jul. 10, 2013.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not Applicable.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The invention relates to compounds useful as sensors in a non-invasive,analyte sensing dressing. The compounds can be meso-unsubstitutedmetallated porphyrins that are sensitive towards oxygen. The metallatedporphyrins can be excited when illuminated at a first wavelength,followed by emission of phosphorescence at a second wavelength whoseemission intensity and/or lifetime can be used as an indicator foroxygen concentration.

2. Description of the Related Art

In a clinical setting, it is often desirable to monitor a patient'shealth by measuring tissue gas levels. Tissue-gas analyses are anessential part of modern patient care and are used in the diagnosis andtreatment of a number of conditions. In particular, measurement oftissue oxygen concentration is heavily relied upon both for generalmonitoring of overall patient health and for treatment of specificconditions, such as ischemia, burns, and diabetic foot syndrome.

In general, there are three main technologies that are used to performblood and tissue gas analyses. A first apparatus, known as a pulseoximeter, is a basic, non-invasive instrument that detects hemoglobinoxygen saturation. Measuring the percentage of oxygen-bound hemoglobinprovides an estimate of arterial oxygenation. The device may be placedon a finger or another body part, and the measurement is accomplished bymonitoring the reflectance or absorbance of incident light. While pulseoximetry is a fast and simple technique, the main drawback is that themeasurement does not measure absolute arterial oxygen concentrations. Inparticular, an inaccurate diagnosis may arise is situations wherehemoglobin concentrations are low or when hemoglobin is bound to aspecies other than oxygen.

A second, more direct measurement of tissue gas levels may be made usingprobe-based systems. Two existing methods based on transcutaneous oxygen(TcpO₂) measurement involve either electrodes or an optical sensorfoil-based patch. As opposed to a pulse oximeter, TcpO₂ measurements canprovide a direct indication of microvascular function as TcpO₂ measuresthe actual oxygen supply available for the skin tissue cells. TcpO₂ alsoresponds to macrocirculatory events, such as a change in blood pressure.

For the more common electrode based system, the TcpO₂ monitor consistsof a combined platinum and silver electrode covered by anoxygen-permeable hydrophobic membrane, with a reservoir of phosphatebuffer and potassium chloride trapped inside the electrode. A smallheating element is located inside the silver anode. In practice, theelectrode is applied to an acceptable site on the skin and is heated to44° C. in order to provide a measurement.

Another commercial system known as the VisiSens™ system combines opticalsensor foils with imaging technology. Fluorescent chemical opticalsensor foils are attached to the sample surface and read outnon-invasively using a microscope. Two-dimensional visualization ofoxygen, pH, or CO₂ distributions over time can be performed withmicroscopic resolution.

Limitations of TcpO₂ systems include the need for two- (or more) pointcalibrations with specially prepared, well-defined samples. The sensormust be in contact with the tissue through a contact liquid. If there isair between the tissue and the sensor, the values will be questionable.For commercial electrode systems, it may take 15-20 minutes after theprobe has been placed on the skin for the TcpO₂ reading to stabilize andit is recommended that calibrations be performed prior to eachmonitoring period, when changing measuring sites, every four hours,and/or every time an electrode has been remembraned. In addition,heating may affect the ability to acquire physiologically relevantmeasurements.

A third approach to monitoring gas levels involves a blood test. Thetest is performed using a blood sample drawn from an artery. The machineused for analysis aspirates this blood from the syringe and measures thepH and the partial pressures of oxygen and carbon dioxide. Thebicarbonate concentration can also be calculated. An advantage of thetest is that results are usually available for interpretation withinminutes. However, the test is invasive, requires a trained practitionerto accurately acquire a sample, and samples must be maintained at roomtemperature and analyzed quickly or results may be inaccurate.

Overall, while there exists a number of methods for monitoring tissuegas levels, each of these methods possesses inherent drawbacks. Itwould, therefore, be desirable to have a system and method formonitoring tissue gas levels that (i) is minimally or non-invasive, (ii)is capable of accurately measuring the actual oxygen supply, (iii)provides fast readout, and (iv) requires minimal expertise so as toenable to be administered by the patient or other non-practitioner. Inparticular, there is a need for compounds that can be used as an oxygensensor in a non-invasive, analyte sensing dressing.

SUMMARY OF THE INVENTION

The present invention overcomes the above and other drawbacks byproviding compounds useful as an oxygen sensor in a non-invasive,analyte sensing dressing. The compounds can be meso-unsubstitutedmetallated porphyrins that are sensitive towards oxygen. The metallatedporphyrins can be excited when illuminated at a first wavelength,followed by emission of phosphorescence at a second wavelength whoseintensity or lifetime can be used as an indicator for oxygenconcentration. A non-invasive, oxygen-sensing dressing including thecompounds may be applied to the surface of tissues such as skin in orderto provide fast, accurate readout without the requirement of specializedtraining.

In one aspect, the present invention provides an interactive, sensing,and therapeutic delivery device designed for the detection andmonitoring of tissue properties that are used to inform a user of thespecific need and spatial location for therapeutic intervention. Incertain embodiments, the sensing and therapeutic delivery device can betriggered to spatially release therapeutics using an interactingportion. Following therapeutic release, the present invention cancontinue to monitor tissue properties in response to treatment.

In accordance with one aspect of the invention, a device is providedthat includes a sensor configured to detect a concentration of ananalyte that includes, but is not limited to molecular oxygen, carbondioxide, nitric oxides, dissolved analytes in plasma, and hydrogen ions.Preferably, the analyte is oxygen. The device also includes a matrixcompatible with the sensor, at least a portion of the matrix beingaccessible to and/or permeable to the analyte. The device includes adressing comprising the matrix and a sensor including a compound of thepresent disclosure, wherein the device emits a signal, such as aphosphorescent signal, in response to the concentration of the analytedetected by the sensor including the compound of the present disclosure.

In accordance with another aspect of the invention, a method ofmanufacturing a device for detecting an analyte is provided thatcomprises selecting a sensor including a compound of the presentdisclosure. The sensor is configured to detect a concentration of ananalyte including but not limited to molecular oxygen, carbon dioxide,nitric oxides, dissolved analytes in plasma or tissue, and hydrogenions. Preferably, the analyte is oxygen. The method also includesselecting a compatible matrix based on a chemical nature of the sensorand enmeshing the sensor in the compatible matrix, at least a portion ofthe matrix being permeable to the analyte. The method further includesincorporating the matrix into a dressing, wherein the dressing isconfigured to emit a signal that varies in response to the concentrationof the analyte detected by the sensor including the compound of thepresent disclosure.

In accordance with yet another aspect of the invention, a kit isprovided for detecting an analyte. The kit includes a dressingcomprising a sensor including a compound of the present disclosure. Thesensor is configured to detect at least one analyte. The dressingincludes a matrix compatible with the sensor and a detector configuredto actuate the sensor and measure a signal as a function of a positionon a surface of the dressing. The analyte may be, but is not limited to,molecular oxygen, carbon dioxide, nitric oxides, dissolved analytes inplasma, and hydrogen ions, and the signal corresponds to the presence ofthe analyte proximate to the surface of the dressing. Preferably, theanalyte is oxygen.

In one form, the compounds of the present disclosure are phosphorescentcompounds wherein the phosphorescence is quenched by oxygen. Aphosphorescent portion of the compound can be converted to the excitedtriplet state by light absorption, followed by return to the groundstate either with light emission (phosphorescence) or by energy transferto molecular oxygen when oxygen molecules are present to collide withmolecules of the phosphorescent compound in the excited triplet state.Therefore, increasing oxygen partial pressure causes an increase in therate of decay of phosphorescence (shorter lifetimes) and a decrease intotal phosphorescence intensity. The compound can be used with an oxygenmeasurement system including a light source, a camera, and a computer.The light source illuminates the compound such that a phosphorescentportion of the compound is converted to the excited triplet state. Lightemission (phosphorescence) can be detected with the camera, and imagesfrom the camera can be placed in the computer memory (which may be, forexample, in a mobile device, camera or smartphone) for calculation andconstruction of an oxygen pressure map from the data. U.S. Pat. No.6,362,175 provides an example method for creating an oxygen pressure mapusing other phosphorescent compounds in which the phosphorescence isquenched by oxygen.

In one embodiment, the compound of the present disclosure is aphosphorescent meso-unsubstituted porphyrin having the Formula (I):

wherein M is a metal, wherein each R is independently an atom or a groupof atoms, and wherein at least one R is —OR¹, wherein R¹ is an atom or agroup of atoms.

In the porphyrin of Formula (I), R¹ may be selected from the groupconsisting of hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkyl carbonyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, heteroaryl, halo, cyano, and nitro. In oneexample of the porphyrin of Formula (I), R¹ is hydrogen. In anotherexample of the porphyrin of Formula (I), R¹ is alkynyl, such as2-propynyl (propargyl). In the porphyrin of Formula (I), a plurality ofR can be —OR¹, and optionally, every R can be —OR¹.

In one example of the porphyrin of Formula (I), R¹ includes a triazolylgroup. The triazolyl group may be bonded to O via an alkyl chain. In oneexample of the porphyrin of Formula (I), R¹ includes an alkylglutamategroup. R¹ may terminate in a pair of alkylglutamate groups. In anotherexample of the porphyrin of Formula (I), R¹ includes a triazolyl group,and R¹ terminates in a pair of ethylglutamate groups, and every R is—OR¹. In one example of the porphyrin of Formula (I), the metal isplatinum or palladium.

The porphyrin of Formula (I) may be an oxygen-sensitive phosphor whoseemission intensity is dependent on oxygen partial pressure. In oneexample of the porphyrin of Formula (I), the porphyrin can be excitedwhen illuminated at a first wavelength in a range of 350-600 nanometers,followed by emission of phosphorescence at a second wavelength in arange of 600-700 nanometers. The first wavelength can be 532 nanometers,and the second wavelength can be 644 nanometers. The first wavelengthcan also be 546 nanometers and the second wavelength can be 674nanometers.

In another embodiment, the compound of the present disclosure is aphosphorescent meso-unsubstituted porphyrin having the Formula (II):

In the porphyrin of Formula (II), R¹ may be selected from the groupconsisting of hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkyl carbonyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, heteroaryl, halo, cyano, and nitro. In oneexample of the porphyrin of Formula (II), R¹ is hydrogen. In anotherexample of the porphyrin of Formula (II), R¹ is alkynyl, such as2-propynyl (propargyl). In the porphyrin of Formula (I), a plurality ofR can be —OR¹, and optionally, every R can be —OR¹.

In one example of the porphyrin of Formula (II), R¹ includes a triazolylgroup. The triazolyl group may be bonded to O via an alkyl chain. In oneexample of the porphyrin of Formula (II), R¹ includes an alkylglutamategroup. R¹ may terminate in a pair of alkylglutamate groups. In anotherexample of the porphyrin of Formula (II), R¹ includes a triazolyl group,and R¹ terminates in a pair of ethylglutamate groups, and every R is—OR¹. In one example of the porphyrin of Formula (II), the metal isplatinum or palladium.

The porphyrin of Formula (II) may be an oxygen-sensitive phosphor whoseemission intensity is dependent on oxygen partial pressure. In oneexample of the porphyrin of Formula (II), the porphyrin can be excitedwhen illuminated at a first wavelength in a range of 350-650 nanometers,followed by emission of phosphorescence at a second wavelength in arange of 700-800 nanometers. The first wavelength can be 594 nanometers,and the second wavelength can be 740 nanometers. The first wavelengthcan be 605 nanometers, and the second wavelength can be 770 nanometers.The first wavelength can also be 600-615 nanometers and the secondwavelength can be 760-800 nanometers.

The present disclosure also provides a method for making a porphyrin.The method includes the step of forming a porphyrin ring via acondensation reaction of a compound of formula (III)

wherein R² is an atom or a group of atoms, wherein R³ is an atom or agroup of atoms, and wherein at least one of R² and R³ is —OR⁴, whereinR⁴ is an atom or a group of atoms. In the method, R⁴ may be selectedfrom the group consisting of hydrogen, substituted or unsubstitutedalkyl carbonyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, heteroaryl, halo,cyano, and nitro. In one version of the method, R² is —OR⁴, and R³ is—OR⁴. In one version of the method, R⁴ is alkyl carbonyl, such as aC₁-C₁₀ alkyl carbonyl, e.g., tert-butyl carbonyl (also known astrimethylacetyl or pivaloyl).

In one version of the method of the present disclosure, the compound offormula (III) is condensed to a tetracyclohexenoporphyrin. Thetetracyclohexeno-porphyrin may be used to synthesize, via metallation, aphosphorescent meso-unsubstituted porphyrin having the Formula (I)above. The tetracyclohexeno-porphyrin may also be used to synthesize,via oxidation and metallation, a phosphorescent meso-unsubstitutedporphyrin having the Formula (II) above. In the porphyrin of Formula (I)or the porphyrin of Formula (II) produced by the method of the presentdisclosure, R¹ may be selected from the group consisting of hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, heteroaryl, halo, cyano, and nitro. R¹ can behydrogen, or R¹ can be alkynyl, such as 2-propynyl (propargyl). In theporphyrin of Formula (I) or the porphyrin of Formula (II) produced bythe method of the present disclosure, a plurality of R can be —OR¹, andoptionally, every R can be —OR′. R¹ can include a triazolyl group. Thetriazolyl group may be bonded to O via an alkyl chain. In the porphyrinof Formula (I) or the porphyrin of Formula (II) produced by the methodof the present disclosure, R¹ may include an alkylglutamate group. R¹may terminate in a pair of alkylglutamate groups. R¹ may include atriazolyl group, and R¹ may terminate in a pair of ethylglutamategroups, wherein every R is —OR¹. In the porphyrin of Formula (I) or theporphyrin of Formula (II) produced by the method of the presentdisclosure, the metal may be platinum or palladium.

The present disclosure also provides a method for measuring oxygenationin tissue of a subject (e.g., an animal, preferably a mammal, mostpreferably a human). The method includes the steps of positioning acompound of Formula (I) or Formula (II) adjacent to the tissue of thesubject, causing the compound to phosphoresce, and calculating an oxygenpressure based on phosphorescence intensity and/or phosphorescencelifetime of the compound. The compound may be associated with a matrixincorporated in a dressing that is placed on a tissue surface (e.g.,skin).

One non-limiting example of the present disclosure is a group of fourmeso-unsubstituted, metallated porphyrins that can be the core componentaround which macromolecular structures can be built that will functionas oxygen sensing materials for a number of biomedical applicationsincluding, but not limited to, cellular level cancer-related hypoxiaimaging and non-invasive oxygenation or perfusion assessment in skinburns, acute and chronic wounds.

The planar structure of these porphyrins of the present disclosure,which is enabled by the lack of substituents in the meso positions oftheir central ring, imparts upon them large absorption cross-sectionsand unusually bright emissive properties, thereby classifying them amongthe most brightly phosphorescent porphyrin molecules. The differentspectral features these molecules exhibit, comprising multiple differentexcitation bands spanning over most of the visible region of thespectrum and different emission profiles, enables them to function as aset of versatile imaging tools compatible with the most widely usedimaging equipment. The compounds also exhibit phosphorescence lifetimesof 40 microseconds to 1 millisecond. Photophysical studies show thatthey exhibit both higher absorption coefficients and phosphorescencequantum yield relative to most known porphyrins. As a result, it isanticipated that these molecules will be highly beneficial in numerousoxygen measurement applications, as they can be excited with a varietyof readily available laser sources, and they output much brighter signalwhich makes signal collection and analysis more efficient.

Synthetically, these molecules can be functionalized with alkyneperipheral groups, making them compatible with a highly efficient andrapid synthetic modification methodology known as 1,3-Huisgencycloaddition (usually termed as “click chemistry”). This elegantsynthetic approach is widely used by researchers who are developingmacromolecular structures for use in biomedical applications, includingthose performing research in the oxygen-imaging field. Notably, the useof the straightforward “click” methodology enables non-specialists tomodify and functionalize the porphyrins using straightforward syntheticprocedures.

This invention offers the research community a variety of oxygen-sensingcores that can be readily and efficiently functionalized within higherorder structures; importantly, these structures will be compatible withcurrently available imaging technology for use in a wide variety ofoxygen sensing applications. Due to the synthetic protocols that existfor growing molecules using “click chemistry” along with the fact thatthere is a large number of researchers having experience with thatmethodology, it is anticipated that the porphyrin molecules describedherein will be extremely useful as essential components for buildingmacromolecular structures for oxygen imaging applications. Additionally,chemically protected synthetic intermediates can become available asoxygen-sensing cores for researchers who wish to further exploresynthetic alternatives that require the introduction of differentperipheral functional groups.

In the compound of the present disclosure, the existence of allalkyne-terminal groups on the periphery in one version of the compound,allows their functionalization via the rapid and synthetically highlyefficient 1,3-Huisgen cycloaddition reaction (usually referred to as“click chemistry”), a methodology in covalent assembly of largemolecules.

The enhanced brightness of the new porphyrins together with the abilityto be readily excitable with common laser lines found in commercialmicroscopes, is a combination of characteristics not being found inproducts that are currently commercially available.

The optimized synthetic protocol developed for the synthesis of the newmolecules, which is at least partly the result of the use of a stableprotecting group during the steps required to modify syntheticintermediates, will allow the production of the final porphyrins inlarge quantities and with high yield.

These and other features, aspects, and advantages of the presentinvention will become better understood upon consideration of thefollowing detailed description, drawings, and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of exemplary components of a dressingin accordance with the present invention.

FIG. 2A is a schematic illustration an embodiment of the presentinvention including a sensing/therapeutic device and an interactingdevice.

FIG. 2B is a schematic illustration of an example of 2-dimensional dataacquired with a device of the present invention.

FIG. 2C is a diagram of an exemplary structure of metallated porphyrinthat may be employed with the present invention.

FIG. 2D is a diagram of an exemplary structure metallatedporphyrin-dendrimer that may be employed with the present invention.

FIG. 2E lists elements included in a formulation for a liquid bandage.

FIG. 3A is perspective illustration showing an example of a stackedstructure in accordance with the present invention.

FIG. 3B is a perspective illustration showing an example of aninterleaved structure in accordance with the present invention.

FIG. 4 is a schematic illustration of an alternate embodiment of adevice of the present invention.

FIG. 5 shows an example of a polymer sensing portion including ameso-unsubstituted platinum porphyrin embedded in a layer of PLGA driedon the surface of a wax film. The polymer sensing matrix is flexible andreadily adheres to the hydrophobic wax film.

FIG. 6A is a schematic illustration of one sensing portion in accordancewith the present invention.

FIG. 6B is a schematic illustration of one therapeutic portion inaccordance with the present invention.

FIG. 7 provides a series of exemplary images showing photobrighteningupon 660 nanometer illumination demonstrating light-mediated therapeuticrelease from PLGA nanoparticles in a biological system.

FIG. 8 illustrates one embodiment of the invention therapeutic deliveryapplication using ultrasonic cleavage of triazole-bridged polymer tofacilitate therapeutic diffusion and release

FIG. 9 is a graph showing the spectral response of an oxygen sensorelement in accordance with the present invention when illuminated with635 nanometer light under different atmospheric conditions.

FIG. 10A is a spatial mapping of oxygen tension in a model ovarian tumorin vitro.

FIG. 10B is a graph showing the calibrated spectral ratio as a functionof oxygen tension. This calibrated ratio can be used for spatial mappingof oxygen tension in biological systems, such as a model ovarian tumorin vitro shown in FIG. 10A.

FIG. 11 provides a series of reports related to an in vivo applicationof the dual O₂/pH sensor on a plain skin surface (a-e), a skin graftdonor site as a model for acute wound healing (f-j), and a chronic wound(k-o). Imaging of pO₂ and pH on intact skin (d and e, respectively)showed homogeneous distribution, while heterogeneity was observed in thecase of a chronic wound imaging (n and o respectively), as reported inMeier et al., Angewandte Chemie International Edition, 50(46):10893-10896, 2011.

FIG. 12 is a flowchart illustrating an embodiment of a method formanufacturing a device of the present invention.

FIG. 13 shows a scheme for the synthesis of a 2,2-dimethylpropanoatefunctionalized, meso-unsubstituted tetracyclohexenoporphyrin.

FIG. 14 shows schemes for the synthesis of (i) metallated propynyloxyfunctionalized, meso-unsubstituted tetracyclohexenoporphyrins, and (ii)metallated propynyloxy functionalized, meso-unsubstitutedtetrabenzoporphyrins.

FIG. 15 shows schemes for assembling the octa-functionalized,meso-unsubstituted metallated tetracyclohexenoporphyrin-based dendrimerof FIG. 2D.

Like reference numerals will be used to refer to like parts from Figureto Figure in the following description of the drawings.

DETAILED DESCRIPTION OF THE INVENTION

Certain implementations of the present invention may include a dressing.Herein, a dressing may include a covering for application to a surfaceand especially for application to a surface of a body part of a patient.The term dressing may also apply to other coverings, such as an ointmentor gauze and may be a solid of liquid. The terms dressing, bandage,covering and related terms may be used throughout the disclosure torefer to a covering.

In one embodiment, the present invention is a bandage/wound dressingdevice 100 having one or more of the following three components: asensing portion 16, a therapeutic portion 14, and an interacting portion20, as illustrated in FIG. 1. The device 100 is contactable and,preferably, removably adhereable to body surface, such as intact and/oropen/damaged tissue. The present device 100 may be used by a “user”,wherein the user may be, for example, a patient's caregiver, aphysician, or even a patient. In one embodiment, the present inventionmay be a device 100 including a sensing/diagnostic portion 16. Thediagnostic portion 16 can be combined with an interacting portion 20(for example, a detector) to measure a signal from the diagnosticportion and provide an output to a user. In another embodiment, thepresent invention may be a device 100 including both a sensing portion16 and a therapeutic portion 14. Referring to FIG. 2A, in yet anotherembodiment, the device 100 may include two distinct but interdependentdevices: a dressing 10 including both diagnostic and therapeuticportions as described above and an interacting portion 20.

Generally, the present invention is capable of performing severalfunctions. Referring to FIG. 2B, the present invention is capable ofgenerating a two-dimensional map 30 of physiologically relevantparameters, where each point on the map corresponds to a scalar valuecorresponding to data relevant to one or multiple analytes in theunderlying tissue, such as the concentration of the analyte or analytes.In one aspect, the map can be read either continuously or point-wise bythe naked eye as a colorimetric sensor response, the quantitative signalcan be stimulated and recorded using the interactive device, or thequantitative signal can be collected by an external digital recordingdevice. In the embodiment illustrated in FIG. 2B, the dark points 32 onthe map are distinct from the white points 42 indicating a variation inthe spatiospecific signal detected. Further, the present invention iscapable of administering doses of therapeutics, such as, but not limitedto, antibiotics, anti-inflammatory agents, biologics, and painmedications. Also, the present invention is capable of administering adose of biomarkers or positron emission tomography tracers along with orinstead of the therapeutics. Even further, the present device is capableof administering these therapeutics in a controlled manner in responseto a specific externally applied stimulus or stimuli. This release canbe accomplished through stand-alone mechanisms independent ofinteracting portion, such as, but not limited to, mechanical pressure,heat, other energetic stimulus or through a stimulus generated by theinteractive device such as, but not limited to, light or ultrasound.Further, the present device is capable of monitoring the quantity oftherapeutics and/or the delivery location on the device's surface whichcan be recorded and/or tracked using either a colorimetric change thatoccurs during or after the delivery process or monitored using theinteracting portion. The present device also is capable of storage,processing, visualization, and/or transmission of data.

Measurements of parameters, such as tissue parameters, are made usingsensor elements that are capable of providing feedback to the userdirectly or indirectly. These sensor elements may not be in directcontact with the tissue. In one aspect, the sensor elements arecontained and/or compartmentalized within the sensing portion, which isin physical contact with the underlying tissue. Readout andquantification of tissue parameters can be made through optical meansfor signal detection from species including, but not limited to,chromophores, fluorophores, or phosphors whose absorption or emissionproperties change based on their passive or active interaction with thetissue. The signal may be responsive to the analytes by modulation ofinelastic scattering of an electromagnetic field, including suchmechanisms as phosphorescence, fluorescence, absorption, and the like.

It is possible to alter and set the excited state lifetimes of a sensor.Excited states of a molecule have intrinsic lifetimes during which theycan be populated. These lifetimes are dependent on an array ofparameters, including molecular structure, temperature, solvationcondition, surrounding molecules, and chemical interactions to name afew. The lifetime of these states can be important in the development ofoptimal sensors, especially in the case of oxygen sensing. For example,tissues in the body contain natural molecules that are fluorescent, suchthat exposure of tissue to certain wavelengths of light can lead tofluorescent emissions. The signal strength of these emissions can belarger or comparable to the emissions of some sensing molecules. Toseparate the emission of the sensor from fluorescence, it is possible tochemically create a sensor whose emissive excited state lifetime islonger than the states of molecules in tissue who give rise tofluorescence emission. If one creates a molecule whose excited state isa so-called triplet state, and this triplet state leads tophosphorescence, then it is possible to temporally distinguish amolecule's phosphorescence from fluorescence. For example, the oxygensensor Oxyphor R2 has a maximum phosphorescence lifetime of almost 1millisecond, a lifetime that is one thousand times longer than thelongest tissue fluorescence source. By using a short temporalillumination (e.g. 1 microsecond long) with a camera system temporallygated to detect signals emitted at longer lifetimes (e.g. 500microseconds after the illumination burst) it is possible to selectivelydetect only the phosphorescence without detecting the fluorescencesignal

Any one or more of these sensing portions may be embedded or enmeshedwithin a compatible matrix that serves to modulate the sensitivity ofthe sensing portions and/or to enhance the stability and useful lifetimeof the sensing portions. This sensor element/matrix combination willhereafter be referred to as the “sensing portion”, with theunderstanding that such terminology encompasses a variety of sensorelement/matrix formulations. In certain embodiments, the sensor elementsinclude a foam, hydrogel, polymer or mixture of multiple ingredients ofuniform or variable porosity and/or heterogeneous/asymmetric orhomogeneous/symmetric dendrimeric structures or layers surrounding eachindividual sensing element. In some embodiments, the sensor elementsinclude the elements illustrated in FIGS. 2C-E. For example, FIG. 2Elists elements included in a formulation for a liquid bandage. Theactive ingredients include benzethonium chloride and the inactiveingredients include amyl acetate, benzalkonium chloride, castor oil, oilof cloves (eugenol, carophyllene), ethanol, n-butyl acetate andnitrocellulose.

Note that optical readout is only one of a variety of informationaldisplays in accordance with the present invention and the inventiontherefore is not necessarily limited to an optical quantificationinterface. In one specific embodiment, a feature of the presentinvention is the containment of these sensing/reporting agents in acompartment or series of compartments separated from the tissue by asemi-permeable layer to prevent direct interaction of the tissue and/orbiological fluids with the sensor elements, as well as with unreleasedtherapeutics. Integral aspects of the semi-permeable membrane includeits ability to physically separate the sensing elements and therapeuticsfrom the tissue, and selectively allow the physiological analyte oranalytes of interest to pass through and interact with the sensorelements and/or the therapeutic-encapsulating matrix. The analyte oranalytes may be any number of biologically relevant species, includingbut not limited to molecular oxygen, carbon dioxide, nitric oxide,dissolved analytes in plasma, and hydrogen ions. The invention'sinteractive features can be implemented through a single “sandwich” typeconstruction, in which the invention's spatial resolution is determinedby the natural diffusion radius of the analyte throughout the matrix, orthrough the formation of multiple compartments physically arrayed acrossthe invention.

If the analyte or analytes of interest are skin-impermeable or areotherwise unable to reach the sensor apparatus (such as gases incapillary beds below the epidermis), one embodiment of the invention cabmakes use of penetrative features that reside on or are arrayed acrossthe bottommost surface of the invention, in contact with the user'stissue, such as needles or microneedles. These penetrative features,will either permeabilize or penetrate whatever occluding layers (forexample, skin, burn eschar) that fall between the bottom layer of theinvention and the analyte(s) of interest, thereby facilitating moreaccurate and more rapid measurements. Another approach is to utilizefractionated laser therapy technology to create micrometer sized holesin the tissue that can enable the diffusion of analytes across thetissue surface. Such an approach can be deployed prior to the placementof the invention or during its use to facilitate to movement of analytesacross normally impermeable tissues. Note that these are only twoembodiments of this feature (that is, a methodology for bringing theanalytes across a diffusion barrier and into contact with the sensorapparatus); many other embodiments and variations may also be used.

Regarding therapeutic encapsulation, in certain embodiments, the presentinvention is capable of delivering one or more therapeutic agents tosurface in contact with the invention. For example, a user can determineto release a therapeutic from the invention due to perceived need orbased on feedback provided by the invention. Therapeutics can beembedded in a degradable matrix that is affixed to, or is part of theinvention. Embedding of therapeutics can be accomplished through anumber of means, such as physical encapsulation (for example, inpoly(lactic-co-glycolic) acid (PLGA), polydimethylsiloxane (PDMS), oranother polymer matrix) or covalent bonding via a reactive chemicallinker that releases therapeutics in response to a physical, chemical,or other stimulus (for example, light, pressure, or thermal changes).The therapeutics can also be embedded in particles, such asnanoparticles. The matrix in which the therapeutic is embedded,hereafter referred to as the “therapeutic apparatus,” can include, butis not limited to, polymers, such as PLGA or polystyrene, a mixture ofmultiple polymers, or other material classes, such as dendrimers,hydrocolloids, or hydrogels. The therapeutic apparatus may be applied toeither specific regions of the invention or the entire invention tofacilitate therapeutic release at user-determined spatial locations onthe inventive device. The invention can also include multiplecompartments, each of which contains a different therapeutic ortherapeutic mixture, all of which can be released by the user atselected spatial locations in a dose-controlled manner throughapplication of the aforementioned external stimulus. As such, theinvention can act to both store and deliver multiple therapeutics,thereby providing, in one embodiment, a novel multi-therapeutic deliveryplatform.

Referring to FIGS. 3A-B, the invention can be constructed in differentgeometrical formats to optimize both sensing and therapeutic deliveryfunctionality, such as, but not limited to, (i) a vertically stackedstructure as illustrated in FIG. 3A, in which the therapeutic apparatus14 resides physically below the sensing apparatus 16; (ii) aninterleaved structure as in FIG. 3B, where the sensing 16 andtherapeutic 14 apparatus are patterned in the same layer; (iii) a mixedstructure in which the sensing apparatus and therapeutic apparatus arephysically combined; and (iv) combinations thereof or variationstherefrom. The mixed structure allows for the therapeutic apparatus toshare common components with the sensor apparatus, as well as for thetwo matrices overlapping and/or otherwise coinciding within the samestructure. In addition, the device 10 can have a top layer 18, which canfunction as a barrier layer or an enhancing layer. In both FIGS. 3A and3B, the device 10 is applied to a surface 12, which can be a surface ofa body part such as skin tissue.

If the therapeutic delivery target is not physically adjacent to theimmediate tissue layer(s) in contact with the invention (such ascapillary beds below the epidermis), one embodiment of the inventionmakes use of penetrative features, such as needles, that reside on orare arrayed across the bottommost surface of the invention, and are incontact with the user's tissue. These features, which may bemicroscopic, will permeate or penetrate whatever occluding layers residebetween the bottom layer of the invention and the therapeutic target.Fractional laser therapy can additionally be used to createmicrometer-sized holes in the tissue that can facilitate the motion oftherapeutics across normally therapeutic-impermeable tissues.Additionally, a chemical agent or combinations of multiple chemicalagents that act to improve tissue permeability, either directly or inresponse to physical stimuli (for example, light, pressure, electricalsignals, or thermal changes) can be built in to the invention tofacilitate the penetration of therapeutics.

Additionally, the invention can be manufactured to be degradable overtime. Many dressings, sutures, and bandages can be configured ormanufactured such that the degraded components are not toxic, are notharmful, and/or are safely absorbable by the body. Such dressings can besafely incorporated into a number of devices, implantable probes, orwithin closed wounds for long-term safe monitoring and/or therapeuticrelease

Regarding therapeutic release, an integral aspect of the therapeuticapparatus is its ability to release therapeutics in response to someexternal stimulus, including but not limited to light, pressure,mechanical force, or thermal changes. As opposed to existing therapeuticdelivery systems, the present invention provides the ability of a userto interactively and spatially control the exact location of therapeuticrelease into tissue from the invention. Whereas existing devices releasetherapeutics across a bandage, dressing or patch, the release propertiesand kinetics of the therapeutic apparatus in this invention can bequantitatively controlled through careful modulation of the appliedexternal stimulus at multiple arbitrary points on the bandage asselected by the user, such that modulation of intensity or duration ofthe external stimulus will result in delivery of a predetermined dose oftherapeutics. A therapeutic apparatus in accordance with the presentinvention may include a polymer containing or composed ofphotoactive/photosensitive molecules that trigger or otherwisefacilitate therapeutic release in response to applied light at a givenbandage position. In this embodiment, the release of differenttherapeutics may be triggered or potentiated for using differentwavelengths of light, thereby creating a simple platform forsimultaneous or sequential administration of multiple differenttherapeutics within the same apparatus. Such a wavelength-triggeredtherapeutic release could be activated by a user to deliver differenttherapeutics to different spatial locations across the apparatus.

Light-based release may be restricted to unique devices such as theinvention's integrative apparatus, so that only use of a specific sourceof light will result in therapeutic release. In this way, the release ofcontrolled substances can be monitored and restricted. Such mechanismscan include optical and/or mechanical approaches. For example,therapeutic release can be initiated only by a predetermined pulse oflight that conforms to specific parameters that may include, for examplepredetermined intensity, duration, polarization, wavelength, andwavelength shifts thereof.

In one embodiment, other interactions, such as continuous illumination,may have no effect on therapeutic release. Therapeutics can also bereleased through mechanical stimulation (such as pressure applied atspatial locations by a user); this pressure can be directly applied tothe invention or induced via other means (that is, pressure wavescreated by light, light pulses, electrical signals, or ultrasound). Suchmechanisms can also be used to permeabilize the underlying tissue forfacilitated penetration through intact tissue.

Therapeutic release kinetics and spatial administration patterns canalso be mediated through the construction of the invention itself. Inone embodiment, the bandage can be constructed to have a singletherapeutic matrix in which the therapeutics are embedded. In anotherembodiment, the invention may be composed of discrete regions, each ofwhich contains a different therapeutic, therapeutic dose, or acombination of the two. In yet another embodiment, each discrete regionhas different therapeutic release kinetics that may be determined by thechemical properties of the selected therapeutic matrix. In all thepreviously described implementations, each discrete region can beconstructed to release a therapeutic singly or in combination with othertherapeutics in response to a variety of user-provided exogenoussignals, such as different wavelengths of light applied to spatiallocations on the invention. In this manner, the invention can suit awide variety of applications. For example, therapeutic release can beachieved with light of different color throughout the visible spectrum.Examples are blue light (450-495 nanometers), green light (495-570nanometers) or orange light (590-620 nanometers).

With respect to the monitoring aspect of the present invention, the samemechanisms that provide for the reporting of tissue parameters canadditionally be used post-treatment to monitor therapeutic response. Ifthe clinical response is not perceived to be adequate, additionalamounts of therapeutic can be released from the invention via theuser-controlled release mechanisms discussed above.

Another aspect of the present invention relates to data storage,processing, visualization, and transmission. The delivery agent orcontrol scheme used to facilitate or trigger therapeutic release can bepart of an interactive, programmable system for controlled, meteredtherapeutic release and reporting. An interacting apparatus configuredto effect pressure, sonic, light, electric, or other energy-basedtherapeutic release can be programmed to release a given amount oftherapeutic in a given time interval at a selected spatial location, andcan be reprogrammed or updated “on the fly” by a caregiver, physician,or remote administrator. The therapeutic delivery system can beinteractively programmed securely over a network, intranet, or over theinternet through wired or wireless communication, or a networked dockingstation, all providing a link to a local computer or remoteserver/computer. This remote link can be used in monitoring the dose andfrequency of therapeutic administration and to inform a physician orcaregiver, and be remotely programmed to allow for changes intherapeutic dose or type. Moreover, the delivery scheme can incorporatesensors that readout regions of the invention to inform a caregiver orclinician of relevant tissue parameters and tissue response. Tissueparameters, treatment response, and all acquired data can be stored,processed, and visualized, either locally or remotely. Data storage,processing, and visualization can be accomplished using the interactingapparatus itself, a docking station, or a computer or mobile device.Thus, the invention also provides a “point-of-care” technology thatenables more effective utilization of in- and out-patient clinicalresources. Such a technological approach may be compatible with effortsin point-of-care medicine, such as monitored home use and kiosk-basedpatient interactions.

FIGS. 2A-B illustrate one embodiment of the device 100 in which adressing 10 has a sensing matrix layer that includes an oxygen-sensitivephosphor whose emission intensity is dependent on oxygen partialpressure. An interacting device 20 includes an actuating portion 22 anda detecting portion 28. The actuating portion generates an actuatingsignal 24 and the detecting portion 28 detects a response signal 26. Inthe illustrated embodiment, the oxygen sensitive phosphor within thedressing 10 can be actuated 24 and a corresponding measure ofphosphorescence 26 can be translated into oxygen concentrations. Thesensing matrix further includes an oxygen-permeable polymeric matrixthat has the phosphor embedded into it and serves as a solid support forthe sensor element. In one embodiment of this invention, the sensorelement may be a construct in which a metallated porphyrin, such asillustrated in FIG. 2C, is physically or covalently encapsulated insidea dendritic layer. The dendritic layer serves to attenuate oxygendiffusion towards the core, thus protecting the porphyrin from excessivequenching and increasing its sensitivity to small changes in oxygenpressures. Excitation and subsequent emission of the phosphor can beused to determine oxygen tension. Specifically, tissue oxygen tension,which is the partial pressure of oxygen (usually reported in mmHg orTorr) within the vapor that is in equilibrium with the tissue ofinterest, can be determined. For example, tissue oxygen tension isproportional to the average oxygen concentration inside the cellular andextracellular components of the tissue and, accordingly, can bedetermined. In another embodiment of the invention, the oxygen sensorcan be excited using indirect excitation via energy transfer from asecond fluorophore. The sensor is embedded into a polymeric matrix thatallows oxygen to freely diffuse through it, and is solely used as asolid support for the sensing element. The sensing apparatus is combinedwith the therapeutic release apparatus, and is separated from thetherapeutic release apparatus via an oxygen-permeable membrane. Incertain embodiments, the sensing apparatus is isolated from ambientoxygen pressure via an oxygen-impermeable membrane that comprises thetop layer of the bandage apparatus as illustrated in FIG. 6A.

As a specific example, a brightly emissive, custom builtmeso-unsubstituted platinum-porphyrin is encapsulated inside a secondgeneration glutamic dendrimer, such as illustrated in FIG. 2D. Glutamicdendrimers are known in the art, and have been successfully employed inincreasing the sensitivity of various metallated porphyrins towardsoxygen. Referring to FIG. 5, the sensor is embedded into a layer ofpoly(lactic-co-glycolic acid) (PLGA) adhered to an oxygen-permeableplastic material that separates it from the release therapeuticapparatus. In this example the porphyrin-dendrimer sensor element can beexcited when illuminated at 532 nanometers, followed by emission ofphosphorescence at 644 nanometers whose intensity can be used as anindicator for oxygen concentration. Of course, other excitation andemission examples are likewise contemplated. For example, otherexcitation/emission examples for different sensors, include (i)excitation at 546 nanometers and emission at 674 nanometers; and (ii)excitation at 594 nanometers and emission at 740 nanometers.

In one embodiment of this invention, a therapeutic agent is embedded ina light actuated polymer patterned on the proximal surface (that is, thesurface closest to the body surface) of a patch (a supporting layer). Inone embodiment, the light actuated polymer contains a photoactivemolecule embedded in the polymer. In another embodiment, the lightactuated polymer contains a light-actuated moiety within the polymerchemical structure. Referring to FIG. 6B, this polymer layer can eitherbe directly adhered to the proximal surface using an adhesive layer, orcan be separated from the adhesive by a permeable membrane layer. Whenirradiated by light, the photoactive compound leads to structuraldegradation of the polymer, facilitating local therapeutic release. Itis known in the art that therapeutics can be readily released frompolymer encapsulation using select wavelengths of light. Photosensitizermolecules used in photodynamic therapy can be encapsulated in PLGApolymer nanoparticles for enhanced uptake and delivery to cells andbiological tissues. In a previous study, the photosensitizer (andfluorophore) 5-ethylamino-9-diethylaminobenzophenothiazinium (EtNBS) wasencapsulated in 120 nanometer diameter PLGA polymer nanoparticles anddelivered to both cells and model ovarian cancer tumors. Whenencapsulated, the close proximity of the photosensitizers acts to quenchabsorption and emission properties of the particles, such that whenencapsulated, illuminated EtNBS-PLGA particles weakly emit fluorescence.When intense red light is delivered to the nanoparticles, the radicalspecies generated by EtNBS act to physically degrade the PLGA polymerstructure, leading to the release of the therapeutic from thenanoparticle. Referring to FIG. 7, the effect is observed asphoto-brightening in samples containing the nanoparticles, as release ofEtNBS negates quenching and results in increased fluorescence emissionintensity.

Another embodiment of a therapeutic release mechanism may involve thecleavage of chemical bonds within the therapeutic apparatus viaultrasound, leading to controlled therapeutic release due to enhanced orfacilitated diffusion through the degraded therapeutic matrix material.In this embodiment, the therapeutic is enmeshed in or chemically bondedto the therapeutic matrix material via chemical moieties known astriazole linkers. Each triazole linker is attached to a long (˜100 kDa)polymer linker such as polymethacrylate (PMA), resulting in theformation of a polymer/triazole network, the porosity of which can betuned chemically. As demonstrated by Bielawski et al., application of 20kHz ultrasonic pulses to triazole/PMA in solution can result inlocalized superheating and the formation of vapor-filled vacuoles, therapid collapse of which resulted in application of attendant stress tothe long polymer chains and subsequent mechanical scission of thetriazole linkers, resulting in the formation of PMA azides and alkynes(J. N. Brantley et al., Science 2011, 333, 1606-1609). This chemicalmechanism is used in this embodiment to cause changes in the fluidityand diffusivity of the therapeutic apparatus, to induce enhancedtherapeutic delivery via locally-facilitated diffusion as illustrated inFIG. 8. In this particular embodiment, the use of PMA is doublyadvantageous, as PMA is known for its ability to absorb many times itsown mass in fluid, making it an absorbent and effective bandage/dressingmaterial. This represents only one embodiment of both thetriazole/PMA-based mechanical bond cleavage approach, as well as onlyone therapeutic apparatus degradation approach. Many other approachesare possible which fall within the scope of the invention, includingalternative encapsulation schemes using different polymers and/or linkergroups as well as other schemes in which the therapeutic is attached tothe matrix polymer directly, rather than enmeshed.

Therapeutics can be released through micro- or macro-structuraldegradation of a therapeutic release matrix. Here, micro-structuraldegradation is defined as structural alterations of a matrix leading totherapeutic release at the nanometer and single micrometer size scales.Macro-structural degradation instead indicates structural alterationsthat occur at size scales larger than 10 micrometers. Multipletherapeutics can be packaged within in each region for the simultaneousrelease of a complete therapeutic regimen. Alternatively, for caseswhere it is not desirable or possible that the therapeutics beco-administered, different therapeutics or therapeutic regimens can bespatially patterned to different regions in the therapeutic apparatus.These different therapeutics or therapeutic regimens may be color-coded,both for indication (for example, red, blue, or green on the distalpatch side) and to differentiate between different releasedtherapeutics. For example, blue light releases a first therapeutic, andred light releases a second therapeutic. Additionally, any lightactuated moiety could be used to trigger a catalytic and/or cascadingsequence that leads to rapid structural degradation. Furthermore, atherapeutic can be contained in a nanoparticle form that is releasedfrom a matrix, such as a polymer, gel, or hydrogel, upon lightactivation via any of the mechanisms previously described.

In other embodiments of the invention, spatioselective therapeuticrelease is accomplished using a bandage apparatus formulated as anadhesive patch that stays affixed to a patient. A user can trigger therelease of therapeutics in a controlled manner through the use of aninteracting apparatus delivering light when held against the bandageapparatus. Following administration, the irradiated region of the patchcan change color to indicate that therapeutic has been released. Asingle patch can hold a multitude of therapeutic releasing regions.

Furthermore, embodiments of the invention can be combined withtherapeutic eluting patch technologies currently in use. Thesedrug-eluting patches include single and double layer drug-in-adhesivepatches as well as reservoir, matrix, and vapor patch designs. Forexample, single and multiple drug-in-adhesive patches could be readilyused in combination with the therapeutic release matrices describedhere. Reservoir, matrix and vapor patch technologies can be embeddedinto embodiments of the invention, including, but not limited to,regions/spaces not containing light-actuated therapeutic releasematrices, layers within the embodiment, or into therapeutic releaseapparatus itself.

As a specific example of a therapeutic apparatus, the anti-inflammatorytherapeutic Diclofenac (2-(2-(2,6-dichlorophenylamino)phenyl)aceticacid) is embedded with the photoactive molecule methylene blue into alayer of PLGA adhered to the proximal surface of a plastic backingmaterial. The patch backing material is composed of a 0.3 cm thick layerof polyvinyl alcohol. The proximal layer of the patch contains anadhesive layer composed of methylcellulose gel. The therapeuticreleasing polymer matrix is patterned over the patch proximal surface in1 cm diameter circular regions each separated by 2 cm. Each circularregion has a corresponding circle that appears on the distal patchsurface to indicate the exact spatial location of the therapeuticreleasing apparatus in the patch. In this example, the spatial locationis marked with cis-azobenzene, which undergoes trans isomerization whenilluminated with 635 nanometer light that results in a color changepost-irradiation. This color change indicates that a specific region ofthe patch has been used.

It should be noted that the use of light in many of these embodimentscan be replaced with mechanical disruption through pressure from anexternal source. For example, the therapeutic release matrix could be abladder filled with a single or multiple therapeutics that is releasedupon its rupture. The flow of material from the bladder would facilitatedelivery of the therapeutic(s) to the patient. In another embodiment,the use of pressure could trigger a material to structurally expand,leading to the release of therapeutic.

In one embodiment of the invention, the interacting apparatus can takethe shape of a hand-held device, such as a pen-shaped applicator, thatcan hold an internal power supply such as a battery. For use withlight-based therapeutic release matrices, this power supply powers abright light emitting diode (LED) affixed to one end. The LED would beselected to emit a specific color of light, for example red light at,for example, approximately 630 nanometers. This LED can be switched onthrough the press of a button on the pen or activated by pressing theinteracting apparatus against a surface. Once activated, the LED wouldremain operational for a set period of time determined by an electroniccircuit inside the pen. In the case of a pressure-induced therapeuticrelease apparatus, an ultrasonic emitter can be powered by the powersource, turned on by the user, and controlled using an electroniccircuit. An electronic circuit used with an energy device such as an LEDor ultrasound emitter can interface with a computer, mobile platform, ornetwork to receive programming instructions, including informationregarding total administrative dose, and number of doses within a setperiod of time. This electronic circuit could also interface with thecomputer, mobile platform, or network to communicate treatmentinformation including number of times used, number of doses received,the historical dose schedule, and the like. The electronic circuit caneither contain a data storage mechanism, or can interface with acomputer, mobile platform, or network to store the information.

One embodiment of the invention is designed for use on patients withopen wounds and is comprised of diagnostic (sensing), treatment(therapeutic), and interacting apparatuses. It is known in the art thatregions of local inflammation in acute and chronic wounds display highrelative oxygen levels in contrast to non-inflamed tissue. An embodimentof the invention that reports tissue oxygenation could be used toidentify and spatially map regions of inflammation in wounds, providingdetailed wound status information to a caregiver or physician. Oncethese specific sites of inflammation are recognized, they can be treatedusing the interactive technology in the invention through user-triggeredrelease of anti-inflammatory therapeutics using the interactingapparatus.

Once therapeutics have been delivered, the oxygenation status of thewound can be monitored to follow the inflammation status of regionstreated, either using the interacting apparatus or other recordingdevices, to provide real-time therapeutic response feedback. A caregiveror physician treating the wound using this invention could then use thedisplayed information to determine the next optimal course of treatment,all without removing the invention and compromising sterility.

The applicants' research has led to the development of rapid-feedbackmolecular probes that measure tissue parameters such as oxygenconcentration (also called oxygen tension).

These oxygen reporting systems can utilize molecules (that is,fluorophores) whose emission properties are insensitive to oxygen alongwith molecules (that is, phosphors) whose emission properties areinfluenced by molecular oxygen concentration. As illustrated in FIG. 9,emission from the fluorophore/phosphor probe can be used to measureoxygen tension in biological systems reversibly with high fidelity. Afirst curve (a) shows an initial emission spectrum from the probe inair, while a second curve (b) shows emission following equilibration ofthe probe in a substantially oxygen free environment (i.e., following anitrogen purge). Finally, a third curve (c) shows emission after onceagain equilibrating the probe in air. As expected, curves (a) and (c)display a similar profile. Such probes can be calibrated so that thespectral ratio between fluorophore and phosphor emission correlate withoxygen concentration. Furthermore, this calibration can be used to readout a map of oxygen concentration in biological samples as shown inFIGS. 10A-B. It is also possible to utilize molecules such as dyes whoselight absorption properties (such as, absorption wavelength orabsorption cross-section) can be modulated by the presence of analytessuch as oxygen for light absorption-based colorimetric oxygenmeasurements.

The present invention provides a system and method for imaging ofmultiple tissue parameters using a wound dressing. The inventionprovided here allows the selective, local release of therapeutics (asdescribed previously and further detailed below) to any part of thetissue or wound covered by the dressing, as well as the subsequentmonitoring of physiological parameters to assess therapeutic response.

The feasibility of imaging tissue parameters (namely pO₂ and pH) using aconventional digital camera, has been demonstrated. The device displayeda wavelength dependent readout, with the data being stored in 3-color(red/green/blue) RGB channels. Referring to FIG. 11, sensing elementswere encapsulated in an analyte-permeable membrane, to form a skin patchfor wound healing monitoring. The method was applied on intact skin aswell as on a chronic wound. In the case of intact skin imaging, ahomogeneous distribution of pO₂ and pH was observed. On the other hand,oxygen and pH values of a chronic wound indicated a sustainedinflammatory phase.

Turning now to FIG. 12, a flowchart is provided to illustrate a method120 for manufacturing a device of the present invention. The exemplarymethod 120 includes, in step 121, a manufacturer or a physiciandetermining whether it is desirable that a given device includes asensing portion. If the individual determines that a sensing componentis desired, in a next step 122, the individual identifies an analyte ofinterest to be sensed by the sensing portion. Once an analyte has beenidentified, in step 123, a sensor suitable for detecting the identifiedanalyte is selected. For example, if molecular oxygen is the analyte ofinterest, a meso-unsubstituted metallated porphyrin molecule designed tobe an effective sensor for oxygen may be selected. The porphyrinmolecule can be excited with a specific wavelength of light and thepresence of oxygen can be detected by measuring a correspondingphosphorescent emission signal.

Having selected a sensor, in step 124, the designer determines whetheror not a therapeutic portion is desired. If a therapeutic portion is tobe included, a therapy of interest is identified in step 125. Theidentified therapy may include the release of pain medication such as anNSAID. Based on the therapy identified in step 125, the therapeutic(s),such as one or more NSAIDs is selected in step 126.

The selection of a therapeutic portion can be done to ensure thecompatibility of the sensor with the matrix, such as will be describedbelow. That is, selection of a therapeutic portion may be done withconsideration to the compatibility of the sensor and, as will bedescribed, the matrix, such that selection of the therapeutic portion isbased on a chemical property of one or both of the sensor and thematrix.

For example, one embodiment involves combining a singlet-oxygendegradable polymer, which can be the basic component of the therapeuticrelease matrix, with an oxygen-independent, free-base porphyrin corethat could generate enough singlet oxygen to trigger the matrixdegradation. A metallated, dendritic analogue of that porphyrin servesas the oxygen-reporting molecule, and is embedded in the sensing matrixselected at step 123. Having inherently different properties, these twomolecules can be actuated using light of different wavelengths; thusallowing on-demand control of oxygen sensing separate from therapeuticrelease. Moreover, dendritic encapsulation can efficiently minimize theamount of singlet oxygen that can reach the therapeutic matrix followinglight-activation of the oxygen-reporting molecule, thus maximizingselectivity in the use of the free-base porphyrin (or anyphotosensitizer) for light-activated therapeutic release.

In step 127, given the selected components, a suitable matrix materialis selected. As described previously, individual matrix materials can beselected for each of the sensing and therapeutic portions or a singlematrix may be selected to support both of the sensing and therapeuticportions.

In one embodiment, the sensor may be enmeshed in the matrix material.Mixing of the sensing matrix components with the sensor may involve theuse an additional, silyl-based component (Triisopropylsilyl chloride orTIPS-Cl) that is similar in structure with those found in the mixturethat forms the matrix (Polydimethylsiloxane or PDMS). For a givenformulation technique to improve the compatibility of the sensor withthe matrix material, the oxygen-reporting molecule of the sensor may beenmeshed within the matrix. Specifically, to achieve a desiredenmeshing, a matrix base may be selected based on a chemical nature ofthe sensor, such that the matrix base is ensured to be desirablycompatible with the sensor and ensures “curing.”

The compatibility between the sensor and its matrix is highly dependenton the structural similarity between the two components. For example,the compatibility may be dependent upon hydrophobicity, polarity ofsurface functional groups, polarity of the entire molecule, type andnumber of charges, molecular weight, stability, reactivity, and otherfactors.

For example, sensor molecules modified with glutamic dendrimers carryhighly polar surface functional groups, which is not compatible with thelow-polarity hydrophobic PDMS matrix. If the sensor molecules were mixedinto the PDMS curing mixture as a dichloromethane (DCM) solution, theywould agglomerate and precipitate out of the curing mixture. Whendimethylformamide (DMF) is used as the solvent for the sensor molecules,better mixing can be achieved with the curing mixture. However, thecuring mixture does not polymerize and form a solid bandage in thepresence of DMF. In accordance with one aspect of the present invention,triisopropylsilyl chloride (TIPS-Cl) can be added as a polar, yethydrophobic, co-solvent to facilitate the mixing of the sensor moleculesand PDMS. It is also structurally similar to the components of the PDMScuring mixture and, therefore, does not interfere with the curingprocess.

Therefore, some general factors that may be considered while matchingthe sensor molecules with the bandage matrix include the chemicalstructures of the sensor and matrix, concentration of the sensormolecule inside the matrix, and potential changes in the matrix'soptical, mechanical, and chemical properties upon mixing the two. Inthis regard, it is advantageous to select the matrix based on a chemicalnature of the sensor or vice versa.

Thus, step 127 stands in contrast to other approaches for coupling asensor with another material, such as using solvents to solubilize anoxygen-reporting molecule in the sensing matrix mixture because suchattempts have been shown to be incompatible as they prevent thepolymerization process known as “curing”, which is the basis for forminga solid and flexible sensing matrix from a viscous mixture of differentcomponents.

Finally, in step 128, the sensing and therapeutic portions and theselected matrix materials are assembled into a device, such as adressing. Notably, a designer can choose to omit either of the sensingand therapeutic portions. For example, in step 121, if the designerdetermines that a sensing portion is not desirable, method 120 indicatesthat the designer should proceed directly to step 124. However, it ispreferable that at least one of the sensing and therapeutic portions isincluded. Therefore, if in step 124, it is determined that a therapeuticportion is not desired, method 120 includes a step 130 in which ifneither sensing nor therapeutic was selected for inclusion in themanufacture of the dressing, the method 120 proceeds to step 121.Alternatively, if at least one of a sensing and therapeutic portion isdesired, method 120 indicates that the designer should proceed to step127.

For embodiments of the present invention that incorporate theaforementioned oxygen reporting probes, the sensing portion can includea matrix composed of a highly breathable polydimethylsiloxane (PDMS)layer where the sensing molecules are enmeshed, and a polyvinylchloride/polyvinylidene chloride (PVC/PVDC) gas-impermeable layer toblock out room oxygen. The use of alternative materials is envisioned,wherein the material is selected based on the desired permeabilitycharacteristics. Examples of such materials are described in Table 1.

TABLE 1 Oxygen Permeability of different polymeric materials (O₂permeability has units of 10⁻¹⁰ cm² s⁻¹ cmHg⁻¹). Polymer O₂ PermeabilitySilicone (PDMS)  76-460 poly(isoprene) (natural rubber) 23.3polyurethane (PU) 1.1-3.6 low density polyethylene (PE) 2.2polycarbonate (PC) 1.4 poly(ethyl methacrylate) (PEMA) 1.2 high densitypolyethylene (PE) 0.3 poly(methyl methacrylate) (PMMA) 0.1 polyvinylchloride (PVC) 0.045 Polytetrafluoroethylene (PTFE) 0.04 polyester (PET)0.02 polyvinylidene chloride (PVDC) 0.005

While permeability is one parameter to consider in the design andconstruction of a dressing in accordance with the present invention, theamount (or thickness) of the material may also be considered. Forexample, the commercial transparent film “Tegaderm” is mainly composedof polyurethane (PU) and acrylate polymers (for example, PMMA, PEMA).They are advertised as breathable and suitable for chronic wounddressing even through PU has a low permeability compared with PDMS.

Based on the aforementioned factors, it is possible to choose apolymeric material (included but not limited to the ones listed inTable 1) or a combination of polymers to be used as the outer layer ofthe embodiment that would prevent room oxygen from interfering with thesensing bandage, while maintaining enough oxygen exchange capabilitythat is necessary for wound healing.

Additionally, it is possible to tune the gas permeability of the barriermaterials to adapt to different clinical applications. Higherbreathability materials can be used in chronic wound dressings designedfor long-term wearing, where sufficient oxygen exchange is essential forthe healing of the wounds. If the bandage is designed for acute woundmanagement, where a quick oxygen reading and other properties of thebandage (exudate absorption, moisture keeping, infection control, andthe like) are desired, less permeable materials can be used as thebarrier layer.

Another aspect of the present invention relates to acute wound and burnmanagement. Traumatic injuries result in acute wounds and burns thatoften require skin grafts or flaps to salvage tissue and limbs torestore function and improve cosmetic outcome. Postsurgical assessmentof perfusion and oxygenation in acute wounds and burns is typicallyqualitative and subjective, relying on episodic assessments such aswound color and temperature, capillary refill, Doppler ultrasound andtouch (Park et al., The Surgical Clinics of North America, 90(6):1181-1194, 2010). These approaches require extensive training, aresubject to operator experience, and can miss critical events due totheir episodic nature, leading to poor surgical outcome. For example,surgical rehabilitation procedures for wounded warriors, such asreconstructive micro-surgery, can fail due to undetected anastomoticfailure, causing loss of perfusion and subsequent ischemia, infarctionand necrosis of the transplanted tissue (Orgill et al., The New EnglandJournal of Medicine, 360(9):893-901, 2009). This is also problematicwhen laying skin over thermal burns, where insufficient debridementresults in the inability to detect adequate graft blood supply, leadingto subsequent graft failure (Meier et al., Angewandte ChemieInternational Edition, 50(46): 10893-10896, 2011). This problem ofpartial graft take has particularly dire consequences in the treatmentof maxillofacial burns, where the loss of grafted skin has profoundrecovery, functional, cosmetic consequences. Current oxygen sensingtechnologies rely on fragile point-by-point measurement tools that arenot easily integrated into surgical settings or post-treatment care.

Problematically, acute wounds and burns are often heterogeneous, withcomplex patterns of inflammation and infection. Inflammation in woundsand burns can lead to poor graft take, while infection can significantlycomplicate the grafting procedure and post-surgical recovery.Inflammation can be readily visualized in acute wounds, as inflamedtissue regions display greater baseline oxygenation (Meier et al.,Angewandte Chemie International Edition, 50(46): 10893-10896, 2011) thanhealthy tissue. Infections result in the depletion of local tissueoxygen as well as changes in the wound bed pH. Spatiotargetedtherapeutic interventions, such as the treatment of inflammation,currently require the removal of wound dressings to enable therapeuticapplication, which can cause a loss of sterility and can disrupt thewound, burn, or graft.

The invention provides a solution to these complex clinical problems.The invention can be built to display an active, real-time map of bothoxygenation and pH across the entire wound or burn site for eithercolorimetric or augmented reality display. The oxygen and pH sensorsthemselves can be embedded in a bandage apparatus and separated from thewound or burn surface via selectively permeable membranes. This ensuresreadout of tissue properties without any risk of interaction with thebandage sensors. This readout is of great importance in the skin graftprocess for the treatment of burns, as the burn site must be adequatelydebrided for a graft to take. Inadequate debridement results in lowperfusion and oxygenation that often results in graft failure. On theother hand, overdebridement can remove critical tissues layers necessaryfor graft take and recovery of function. A bandage apparatus capable ofvisualizing perfusion and oxygenation across a burn site would savenumerous surgical protocols and allow physicians to better plan theirinterventions to maximize graft success and minimize patient impact.Equally important, a bandage apparatus that can allow for the selective,spatial administration of therapeutics will allow caregivers to treatinflammation and infection without bandage removal and the accompanyingdisruption of the burn and loss of sterility.

To allow for therapeutic intervention, a separate portion of theinvention contains therapeutics embedded in light-degraded polymerstriggered by specific wavelengths of light. An interacting apparatuscontaining various colored LEDs is applied to the sensing andtherapeutic bandage apparatus, with a specific color LED triggering theselective release of a specific therapeutic. For example, regions ofinflammation can be exposed to blue light to release ananti-inflammatory, while an infected region in the same wound sight canbe treated with antibodies through red-light illumination. Thus, theinvention-provided oxygenation and/or pH mapping allows forspatiotargeted delivery of needed therapeutics to affected tissueregions, without ever removing the bandage or compromising sterility.Moreover, since the invention remains on the wound, the same oxygen andpH mapping capability can track the recovery process, providingclinicians with real-time feedback for accurate wound recoveryassessment.

Another aspect of the present invention relates to chronic wounds (forexample, ulcers) management. Chronic wound management is a challenginghealthcare problem, with an estimated 2% of the world populationsuffering from chronic wounds or associated co-morbidities (Gethin etal., Wounds UK, 3(3):52-55, 2007). Major sources of chronic woundsinclude venous and/or arterial ulcers, decubitus ulcers (bed/pressuresores), and diabetic ulcers. Although chronic wounds afflict patientsfrom all demographics and age groups, the elderly and diabetics areparticularly effected, accruing collective wound management costs inexcess of $10 billion annually (Snyder et al., Clinics in dermatology,23(4):388-95, 2005).

The present invention provides a platform that offers severalapplications in the management of chronic wounds. As a first example,chronic wound patients report severe, persistent pain that adverselyaffects their activity level and quality of life (Jorgensen et al.,Official Publication of the Wound Healing Society [and] the EuropeanTissue Repair Society, 14(3):233-9, 2006). Although a wide variety oforal pain medications are available for pain management, pain fromchronic wounds such as venous leg ulcers is often undertreated due topatient frailty, contraindication or poor tolerance of systemicanalgesics, or simple reluctance to take more medicine. These patientsalso report severe pain associated with frequent bandage changes(Jorgensen et al., Official Publication of the Wound Healing Society[and] the European Tissue Repair Society, 14(3):233-9, 2006).Additionally, the World Health Organization (WHO) guidelines for painmanagement suggest following a “pain relief ladder,” starting from thelowest level (that is, non-narcotic non-steroidalanti-inflammatory-NSAIDs) and moving upwards to local and/or systemicopiates as needed. Although Jorgensen et al. recently repotteddevelopment of a NSAID-eluting foam wound dressing for treatment ofvenous leg ulcers, this solution offers only the lowest level of painmanagement (Jorgensen, Bo, et al., (2006) Journal of Wound Repair andRegeneration, vol. 14, iss. 3, pp. 233-239). Furthermore, the presenceof a wound dressing on the wound bed precludes the possibility offurther local pain management without bandage removal.

An embodiment of the invention can function as a tiered chronic woundpain management platform, offering the ability to treat pain on-demandspatiospecifically. In one embodiment of the invention, the therapeuticapparatus within a bandage apparatus contains NSAIDs, which can eitherbe constitutively eluted or eluted in response to a particularwavelength of light administered by the interacting apparatus (forexample, green light). In this same embodiment, the therapeuticapparatus also contains an additional drug, representing a “step up” onthe WHO pain ladder (for example, fentanyl, buprenorphine, or morphine),that is eluted from the therapeutic apparatus in response to a differentwavelength of light (for example, blue light). Thus, patients orcaregivers could avoid unnecessary consumption of opiate therapeutics,relying instead on spatiospecific therapeutic administration on anas-needed basis.

Additionally, the frequency of dressing removal and wound examinationcan be further reduced by the invention's capacity as a spatiospecificsensor of physiologically relevant parameters, such as pH. It is knownin the art that pH can be correlated to the clinical stage of pressureulcers (Gethin et al., Wounds UK, 3(3):52-55, 2007) and could thereforebe used to monitor wound healing as well as identify potential problems,such as infection, without the painful, labor-intensive, andpsychologically problematic process of repeated dressing removal.Furthermore, early identification of wound regression would accelerateidentification of wound pathologies, intervention, and treatment,thereby potentially preventing co-morbidities such as infection. pH alsohas been shown to correlate to oxygen tension, itself an importantindicator of wound healing.

A specially-tailored bandage apparatus can be additionally used tomonitor and display lipopolysaccharides (LPS) as an indication ofinfections and release antibiotics on-demand. Moreover, the managementand surgery of chronic wounds is similar to what is found in thetreatment of burn grafts. Thus embodiments of the invention could beused in a similar fashion to verify adequate debridement and monitorwound beds post-operatively for infection without bandage removal.

Another aspect of the present invention relates to pain management. Theinvention can be used to avoid the use of needles, catheters, infusionand syringe pumps while the associated interacting apparatus would allowremote telemetry and monitoring. Therefore, pain medication could becustomized and calibrated in real-time to patient's pain intensity asmeasured by the pain scale. Accurate dosimetry and calibration has thepotential of decreasing side effects.

Another aspect of the present invention relates to accelerated on-demandtherapeutic delivery. Many currently used therapeutic delivery patchesand bandages use reservoirs saturated with a given drug that isseparated from the patient's skin by a membrane. For this type of patch,the membrane is chosen such that the rate of therapeutic diffusionthrough the membrane is lower than that of the protective skin layercalled the stratum corneum. This ensures that the elution of thetherapeutic through the membrane occurs at a rate allowing fortransdermal delivery. Less expensive designs incorporate adhesive layersthat accomplish the same effect, where the adhesive acts as both areservoir and a diffusion-controlling matrix (Prausnitz et al., Naturebiotechnology, 26(11): 1261-8, November 2008).

The key limitation of these approaches is that the delivery rate of thetherapeutic is ultimately bound by the transdermal therapeutic transportrate. This can be acceptable for slow-therapeutic release systems or formarginally hydrophilic therapeutics. However, most existing drugs aresignificantly hydrophobic, and in many cases need to be delivered in asingle dose instead of extended timed release. Also problematic is thatpatches based on diffusion are environmentally sensitive: fentanylpatches accidentally worn in a hot shower, for example, lead to patientdeaths due to increased diffusion at higher temperatures.

A solution to these issues would be a mechanism that could temporarilydisrupt the stratum corneum to facilitate increased therapeuticdiffusion. One proposed mechanism would be to disrupt the stratumcorneum using photodynamic therapy (Dougherty et al., Journal of theNational Cancer Institute, 90(12):889-905, 1998). In this approach, ahydrophobic photosensitizer with limited dermal penetration would betaken up by the stratum corneum. Under illumination, reactive radicalspecies released by the photosensitizer would react, opening up poresand fissures in the stratum corneum through which therapeutics couldtravel. Short-wavelength, blue light could additionally be used forphotoactivation to limit the depth of reactive radical specie generationto only the stratum corneum.

Following disruption of the stratum corneum, therapeutics in theinvention could either (1) directly then flow into the tissue, (2) bereleased through a semi-permeable membrane, or (3) be triggered forrelease via a secondary membrane containing a different photosensitizer.The first case, direct flow of therapeutics, would be useful forshort-term, instant release of therapeutic agents not compatible withexisting transdermal approaches. This case would also be useful for thedelivery of therapeutics in special populations, such as children or theelderly, where standard administration approaches are either difficultor impossible to use.

Release through a semi-permeable membrane could be used to buildembodiments of the invention with a selective “on” mechanism. Withoutthe photodynamic action to facilitate local breakdown of the stratumcorneum, patch and bandage embodiments of the invention would remainentirely dormant. Only illumination with light would enable the releaseof therapeutic agents. This approach could be of use in situations thatrequire self dosing, such as home-care, or be used for low-cost, thirdworld applications where sunlight can be used to activate patch and/orbandage embodiments of the invention.

Another aspect of the present invention relates to vaccine delivery. Theneed for safe and efficient vaccine administration depends onengineering simple tools for transdermal delivery. One challenges toovercome is the limited penetration of materials through the stratumcorneum. A number of different techniques that facilitate transcutaneousdrug delivery are known in the art. Such drug delivery methods disruptthe stratum corneum, for example, through the use of microneedles(Bariya et al., Journal of Pharmacy and Pharmacology, 64(1):11-29, 2012;Vrdoljak et al., Journal of Controlled Release, 159(1):34-42, 2012) andablative fractional lasers (AFL) (Chen et al., Journal of ControlledRelease, 159(1):43-51, 2012), which are minimally invasive and notentirely painless, and/or require skin pretreatment.

Skin patches for transcutaneous vaccine delivery offer the advantages ofbeing a noninvasive, painless and cost-effective method of immunizationthat does not require the assistance of highly trained health carepersonnel. In one example, a hydrogel patch is used in transcutaneousvaccination for tetanus and diphtheria (Hirobe et al., Vaccine, 30(10):1847-1854, 2012). Octyldodecyllactate, which is an absorption enhancerthat disrupts the lipid bilayer of the stratum corneum (Hood et al.,Food and Chemical Toxicology, 37(11): 1105-1111, 1999), was used in thepreparation of the patch in order to promote the transmission of thevaccines through the skin. Embodiments of the invention that make use oflight-activated skin penetration enhancement, as discussed above, couldallow for the release of a vaccine from a skin patch apparatus for thecontrolled release of vaccine doses. In one embodiment of the invention,this could be achieved with polymer cages encapsulating vaccines thatare degraded by applying light of a specific wavelength. Vaccine releaseoccurs either simultaneously, or following light-activated skinpenetration by using polymeric matrices with different degradationpathways.

Vaccine administration using this embodiment of the invention isapplicable in areas such as pediatrics, where having a painless methodthat requires minimal pretreatment is essential when dealing with youngpatients. Moreover, it can help fight the problem of disease outbreaksin developing countries, as a simple and inexpensive way to rapidlyvaccinate large populations without the need of trained healthcarepersonnel. In this case, light-degradable polymeric matrices that areactivatable by sunlight can be used, and vaccination can be simplyaccomplished by exposure to sunlight.

Many additional applications exist, including but not limited to (i)pain therapeutics for palliative and chronic care, both in hospitalsettings and for home care; (ii) localized and spatiospecificadministration of steroidal anti-inflammatory to patients suffering fromchronic inflammation, sports-related injuries, or rheumatoid arthritis;(iii) antibiotics and/or anti-inflammatory therapeutics in COPD patientsfor use in ICUs; (iv) therapeutic administration customized for selectpatient populations such as pediatric, neonate, or geriatric patients;and (v) automated, remote administration of a therapeutic ortherapeutics to patients in locations where medical care and/orself-administration is not an option (i.e., fighter or commercial jetpilots, unconscious/incapacitated soldiers on the battlefield, and thelike).

It is therefore an advantage of the present invention to promote newareas of investigation in the fields of pain release (postoperative,acute, chronic, and palliative) and vaccination (preventive, curative).Another advantage of the present invention is to provide customizedtherapeutic approaches in pediatric medicine, geriatrics, andpost-trauma care. Yet another advantage of the present invention iscontribute to the establishment of clinically powerful and user-friendlyhome care and telemonitoring programs.

The invention is further illustrated in the following Examples, whichare presented for purposes of illustration and not of limitation.

EXAMPLES Example 1

Turning now to FIG. 13, a Scheme for the synthesis of a2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetracyclohexenoporphyrin 7 is shown. The reagents and conditionslabelled in FIG. 13 can be abbreviated as follows: i) 1,3-butadiene(excess), r.t., 2d, 90%; ii) K₂OsO₄, K₃Fe(CN)₆, K₂CO₃, CH₃SO₂NH₂,tBuOH/H₂O (1/1), r.t., overnight, 95%; iii) (CH₃)₃CCOCl,4-Dimethylaminopyridine, pyridine, CH₂Cl₂, r.t., overnight, 75-80%conversion; iv) CNCH₂CO₂tBu, tBuOK, THF, r.t., 4h, 81%; v) TFA, r.t. 30min, 52%; vi) p-TsOH(monohydr.), formaldehyde (37% in water), benzene,reflux (Dean-Stark condenser), 8h, 42%.

Ethynyl p-tolyl sulfone 1 was reacted with an excess of 1,3-butadiene atroom temperature for two days to form1-(cyclohexa-1,4-dien-1-ylsulfonyl)-4-methylbenzene 2 at 90% yield. Thecyclohexadienyl p-tolyl sulfone 2 was reacted with K₂OsO₄, K₃Fe(CN)₆,K₂CO₃, CH₃SO₂NH₂, tBuOH/H₂O (1/1) at room temperature, overnight to form4-tosylcyclohex-4-ene-1,2-diol 3 at 95% yield. The diol 3 was reactedwith (CH₃)₃CCOCl, 4-Dimethylaminopyridine, pyridine, CH₂Cl₂ at roomtemperature overnight to yield a 75-80% conversion to4-tosylcyclohex-4-ene-1,2-diyl bis(2,2-dimethylpropanoate) 4. Thesubstituted cyclohexene 4 was reacted with CNCH₂CO₂tBu, tBuOK, THF atroom temperature for 4 hours to form the t-butoxycarbonyl substituted,2,2-dimethylpropanoate functionalized 4,5,6,7-tetrahydro-2H-isoindole 5at 80% yield. The tetrahydro-2H-isoindole 5 was reacted withtrifluoroacetic acid at room temperature for 30 minutes to form4,5,6,7-tetrahydro-2H-isoindole-5,6-diyl bis(2,2-dimethylpropanoate) 6at 52% yield. The tetrahydro-2H-isoindole 6 was condensed using p-TsOH(monohydrate), formaldehyde (37% in water), benzene, reflux (Dean-Starkcondenser) for 8 hours to form 2,2-dimethylpropanoate functionalized,meso-unsubstituted tetracyclohexenoporphyrin 7 in 42% yield.

Example 2

Turning now to FIG. 14, Schemes for the synthesis of (i) metallatedpropynyloxy functionalized, meso-unsubstitutedtetracyclohexenoporphyrins 8B, 9B and (ii) metallated propynyloxyfunctionalized, meso-unsubstituted tetrabenzoporphyrins 12B, 13B areshown.

In (i), the 2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetracyclohexenoporphyrin 7 from FIG. 13 was refluxed with platinumchloride or palladium chloride to obtain a 2,2-dimethylpropanoatefunctionalized, meso-unsubstituted tetracyclohexenoporphyrin platinumcomplex 8A or a 2,2-dimethylpropanoate functionalized,meso-unsubstituted tetracyclohexenoporphyrin palladium complex 9A. The2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetracyclohexenoporphyrin platinum complex 8A and the2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetracyclohexenoporphyrin palladium complex 9A were reacted with lithiumaluminum hydride in a mixture of dry dichloromethane and THF, at roomtemperature for 4 hours, to form the corresponding octa-hydroxy,meso-unsubstituted tetracyclohexenoporphyrin complexes 10. Theocta-hydroxy, meso-unsubstituted tetracyclohexenoporphyrin complexes 10were reacted with sodium hydride and propargyl bromide in dryN,N-Dimethylformamide, at room temperature overnight, to form thecorresponding octa-propyloxy functionalized, meso-unsubstitutedtetracyclohexenoporphyrin platinum complex 8B and the octa-propyloxyfunctionalized, meso-unsubstituted tetracyclohexenoporphyrin palladiumcomplex 9B.

In (ii), the 2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetracyclohexenoporphyrin 7 from FIG. 13 was oxidized with2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to obtain the2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetrabenzoporphyrin 11 which was refluxed with platinum chloride orpalladium chloride to obtain a 2,2-dimethylpropanoate functionalized,meso-unsubstituted tetrabenzoporphyrin platinum complex 12A or a2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetrabenzoporphyrin palladium complex 13A. The 2,2-dimethylpropanoatefunctionalized, meso-unsubstituted tetrabenzoporphyrin platinum complex12A and the 2,2-dimethylpropanoate functionalized, meso-unsubstitutedtetrabenzoporphyrin palladium complex 13A were reacted with lithiumaluminum hydride in a mixture of dry dichloromethane and THF, at roomtemperature for 4 hours, to form the corresponding octa-hydroxy,meso-unsubstituted tetrabenzoporphyrin complexes 14. The octa-hydroxy,meso-unsubstituted tetrabenzoporphyrin complexes 14 were reacted withsodium hydride and propargyl bromide in dry N,N-Dimethylformamide, atroom temperature overnight, to form the corresponding octa-propyloxyfunctionalized, meso-unsubstituted tetrabenzoporphyrin platinum complex12B and the octa-propyloxy functionalized, meso-unsubstitutedtetrabenzoporphyrin palladium complex 13B.

Example 3

Turning now to FIG. 15, Schemes for the synthesis of an octasubstituted,meso-unsubstituted tetracyclohexenoporphyrin metal complex 19 (alsoshown in FIG. 2D) are shown. First, a generation-2 glutamic dendron wasassembled using functionalized glutamic acid monomers (top of FIG. 15),and then the generation-2 glutamic dendron was reacted with thealkyne-terminated porphyrin core in a single step (bottom of FIG. 15)using a quick and efficient copper-catalyzed reaction known as Huisgen1,3-dipolar cycloaddition. The reaction occurred between the alkynegroups on the porphyrin and the azide groups on the glutamate dendron.

Still referring to FIG. 15, a diethyl glutamate (diethyl2-aminopentanedioate) 16 was reacted with the dicarboxylic acid propylazide 17 to form the azide 18, a generation-2 glutamic dendron. Theocta-propyloxy functionalized, meso-unsubstitutedtetracyclohexenoporphyrin platinum complex 8B and the octa-propyloxyfunctionalized, meso-unsubstituted tetracyclohexenoporphyrin palladiumcomplex 9B were reacted with the azide 18 to form the octasubstituted,meso-unsubstituted tetracyclohexenoporphyrin metal complexes 19, theplatinum containing version of which can be excited when illuminated ata wavelength of 532 nanometers, followed by emission of phosphorescenceat a wavelength of 644 nanometers. For the palladium containing version,the corresponding excitation/emission wavelengths are 546/674 nm.

In a similar manner, the octa-propyloxy functionalized,meso-unsubstituted tetrabenzoporphyrin platinum complex 12B and theocta-propyloxy functionalized, meso-unsubstituted tetrabenzoporphyrinpalladium complex 13B can be reacted with the azide 18 to formoctasubstituted, meso-unsubstituted tetrabenzoporphyrin metal complexes.

Thus, the invention provides compounds useful as a sensor in anon-invasive, oxygen sensing dressing. In one form, the compounds can bemeso-unsubstituted metallated porphyrins that are sensitive towardsoxygen. The metallated porphyrins can be excited when illuminated at afirst wavelength, followed by emission of phosphorescence at a secondwavelength whose intensity can be used as an indicator for oxygenconcentration.

Although the present invention has been described in detail withreference to certain embodiments, one skilled in the art will appreciatethat the present invention can be practiced by other than the describedembodiments, which have been presented for purposes of illustration andnot of limitation. Therefore, the scope of the appended claims shouldnot be limited to the description of the embodiments contained herein.

1-66. (canceled)
 67. A porphyrin having the Formula (7):

wherein each R is independently an atom or a group of atoms, and whereinat least one R is —O(C)OR′, wherein R′ is optionally substituted alkyl.68. The porphyrin of claim 67 wherein: R′ is dialkyl alkyl.
 69. Theporphyrin of claim 67 wherein: R′ is dimethyl alkyl.
 70. The porphyrinof claim 67 wherein: R′ is dimethyl ethyl.
 71. The porphyrin of claim 67wherein: every R is —O(C)OR′, and R′ is a t-butyl group.